Normal as well as neoplastic cells invade surrounding tissues by mobilizing proteolytic enzymes that allow them to degrade the structural barriers established by the extracellular matrix. One group of proteinases, known as the matrix-degrading metalloproteinases or MMPs, is currently believed to play a prominent role in matrix remodeling events since these enzymes can, in concert, degrade all of the major proteinaceous components of the extracellular matrix including collagens, elastin and proteoglycans. Recently, the first membrane-anchored member of the MMP family, termed the membrane type-1 MMP (MT1-MMP), was identified and shown to be expressed not only in normal mesenchymal/epithelial cell types, but also at heightened levels in a variety of human carcinomas. Based on the ability of MT1-MMP to activate progelatinase A and/or collagenase-3, it has been postulated that this metalloproteinase axis may act as the master switch that regulates the expression of the tissue-invasive phenotype. However, increasing evidence suggests that MT1-MMP plays a direct and critical - role in regulating cell-matrix interactions. More recent data now indicate that MT1-MMP activity may be complemented by a second, membrane-anchored MMP, termed MT2-MMP. While little is known with regard to MT2-MMP structure or function, the protease is postulated to play a dominant, and heretofore, unsuspected role in regulating normal and neoplastic epithelial cell function. To this end, we seek to use a series of molecular, genetic and cellular approaches to i) characterize MT2-MMP structure and function relationships in extracellular matrix degradation and invasion, ii) define the relative roles of MT2-MMP and MT1-MMP in normal tissue development and iii) characterize the functional impact of MT2-MMP and/or MT1-MMP on cancer growth, invasion and metastasis in vivo. These studies should provide new insights into the role of the MT-MMPs in normal as well as neoplastic cell populations and define their potential importance as targets for novel therapeutic interventions. PUBLIC HEALTH RELEVANCE: These studies should provide new insights into the role of the MT-MMPs in normal and neoplastic cell populations and define their potential importance as targets for novel therapeutic interventions.